甲基乙二醛合酶和磷酸丙糖异构酶的功能特异性：量子力学/分子力学联合分析

Functional specificities of methylglyoxal synthase and triosephosphate isomerase: a combined QM/MM analysis.

作者信息

Zhang Xiaodong, Harrison David H T, Cui Qiang

机构信息

Department of Chemistry and Theoretical Chemistry Institute, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.

出版信息

J Am Chem Soc. 2002 Dec 18;124(50):14871-8. doi: 10.1021/ja027063x.

DOI:10.1021/ja027063x

PMID:12475328

Abstract

Combined SCC-DFTB/CHARMM calculations were carried out to analyze the origin for the functional specificities of triosephosphate isomerase (TIM) and methylglyoxal synthase (MGS). The two enzymes bind to the same substrate, dihydroxyacetone phosphate (DHAP), and have rather similar active sites. However, they catalyze different reactions; TIM catalyzes the isomerization of DHAP to glyceraldehyde 3-phosphate (GAP), while MGS catalyzes the elimination of phosphate from DHAP. Similar to previous suggestions, the calculations confirmed that GAP formation is prohibited in MGS due primarily to the reduced flexibility of the catalytic base (Asp 71) compared to that in TIM (Glu 165). For the suppression of phosphate elimination in TIM, the calculations show that the widely accepted stereoelectronic argument that invokes the different phosphoryl torsion angles observed in the X-ray structures of inhibitor complexes of the two enzymes is not as important as electrostatic contributions from the protein and water molecules surrounding the phosphoryl.

摘要

进行了结合SCC-DFTB/CHARMM计算，以分析磷酸丙糖异构酶（TIM）和甲基乙二醛合酶（MGS）功能特异性的起源。这两种酶结合相同的底物磷酸二羟丙酮（DHAP），并且具有相当相似的活性位点。然而，它们催化不同的反应；TIM催化DHAP异构化为3-磷酸甘油醛（GAP），而MGS催化从DHAP中消除磷酸。与之前的观点相似，计算结果证实，MGS中GAP的形成受到抑制，主要原因是与TIM（Glu 165）相比，催化碱基（Asp 71）的灵活性降低。对于TIM中磷酸消除的抑制，计算结果表明，广泛接受的立体电子学观点，即援引在两种酶的抑制剂复合物的X射线结构中观察到的不同磷酰扭转角，不如围绕磷酰的蛋白质和水分子的静电作用重要。